Afferent plasticity underlying urethral and pelvic pain

由于目前治疗下尿路（LUT）疼痛性疾病（如间质性疾病）的选择有限， 膀胱炎（1C）或慢性盆腔疼痛综合征（CPPS），对开发新的治疗方法有很大的需求 战略由NIH资助“尿道和骨盆疼痛的传入可塑性”R 01 DK 57267，1999年1月9日- 2003年8月31日，我们发现：（1）内脏神经传入纤维群存在相当大的异质性， 通向膀胱/近端尿道的通路和通向外尿道括约肌（EUS）/骨盆的体神经通路 （2）膀胱/尿道组织炎症和阴部体神经损伤可引起 膀胱/尿道功能亢进与C纤维传入兴奋性亢进有关，这是由于不同类型的 电压门控性K+电流。因此，本项目的目标是进一步确定诱导 传入性兴奋过度与LUT疼痛相关，特别关注其作用和神经营养因子依赖性 C-纤维传入的调节（即，肽能和非肽能群体）。我们将首先研究 核糖体失活毒素皂草素与异凝集素B4结合，理论上可以抑制传入 通过IB 4结合的非肽能C-纤维传入途径传递。这将使我们能够识别功能 非肽能C纤维传入神经在由LUT不同区域引起的疼痛状况中的作用。其次，我们将 探讨两种不同的神经营养因子（NGF和GDNF）在C纤维形成中的调节作用 过度兴奋参与LUT疼痛，因为这两个因素据报道调节的功能特性， 肽能和非肽能C-纤维传入途径。第三，我们将试图阐明分子 由于Kv的表达改变，负责C纤维超兴奋的电压门控K+（Kv）通道的身份 在我们以前的研究中，通道被证明有助于LUT疼痛条件下的C-纤维过度兴奋。 本研究采用动物尿道或盆腔疼痛模型，其具体目的是：I）研究 使用皂草素缀合物靶向LUT疼痛病症的非肽能C纤维传入途径; II） 研究NGF/GDNF及其抗体对LUT疼痛状况的影响;和III）鉴定 LUT传入神经元Kv通道亚单位的表达及其与K+电流亚型减少的关系 和C纤维传入神经元过度兴奋。该研究计划的长期目标是确定 详细的机制和新的，有效的治疗目标的疼痛条件的LUT。这是公认的高 优先考虑IC/CPPS患者的泌尿科护理。

Because of current, limited options for treating painful disorders in the lower urinary tract (LUT) such as interstitial cystitis (1C) or chronic pelvic pain syndrome (CPPS), there is a great demand for the development of new treatment strategy. Supported by NIH grant "Afferent plasticity underlying urethral and pelvic pain" R01 DK57267, 09/01/1999- 08/31/2003, we found that; (1) there is a considerable heterogeneity in afferent fiber populations in visceral neural pathways to the bladder/proximal urethra and somatic neural pathways to the external urethral sphincter (EUS)/pelvic floor, and (2) tissue inflammation of bladder/urethra and nerve injury of somatic pudendal nerves can induce bladder/urethral hyperactivity associated with C-fiber afferent hyperexcitability due to a reduction in different types of voltage-gated K+ currents. Thus, the goals of this proposed project are to further identify the mechanismsinducing afferent hyperexcitability related to LUT pain, especially focusing on the role and neurotrophic factor-dependent regulation of C-fiber afferents (i.e., peptidergic and non-peptidergic populations). We will first examine the effects of the ribosome-inactivating toxin saporin conjugated with isolectin B4, which can theoretically suppress afferent transmission via IB4-binding, non-peptidergic C-fiber afferent pathways. This will allow us to identify the functional role of non-peptidergic C-fiber afferents in pain conditions arising from different regions of the LUT. Secondly, we will explore the regulatory role of two different neurotrophic factors (NGF and GDNF) in the emergence of C-fiber hyperexcitability involved in LUT pain since these two factors reportedly modulate the functional properties of peptidergic and non-peptidergic C-fiber afferent pathways, respectively. Thirdly, we will seek to elucidate molecular identities of voltage-gated K+ (Kv) channels responsible for C-fiber hyperexcitability since altered expression of Kv channels was shown to contribute to C-fiber hyperexcitability in LUT pain conditions in our previous study. The Specific Aims of this proposal using animals models of urethral or pelvic pain are: I) to investigate the effects of targeting non-peptidergic C-fiber afferent pathways on LUT pain conditions using saporin conjugates; II) to investigate the effects of NGF/GDNF and their antibodies on LUT pain conditions; and III) to identify the changes in expression of Kv channel subunits in LUT afferent neurons and the correlation with a reduction of K+ current subtypes and C-fiber afferent neuron hyperexcitability. The long-term objectives of the research program are to identify the detailed mechanisms and new, effective therapeutic targets for pain conditions in the LUT. This is recognized as a high priority in the urologic care of patients with IC/CPPS.